Candida albicans is a commensal fungus residing in the oral cavity, the gastrointestinal tract, and the vagina of humans and other warm-blooded animals. It is also an opportunistic pathogen with a disease spectrum ranging from mild superficial infections in overall healthy people to wide-spread, and life-threatening systemic infections in patients with compromised immunity due to underlying disease or immunosuppressive therapy. C. albicans is the 4th most common microorganism causing nosocomial blood stream infections, therefore representing a serious public health challenge of increasing medical and socio-economic importance. Our working hypothesis is that the adaptation of C. albicans through genetic changes during infection may play a bigger-than- anticipated role in host-pathogen interactions. In previous work, we detected higher rates of phenotypic and chromosome-level genetic variation following passage of C. albicans in vivo than after propagation for a similar number of generations in vitro, while the rate of short-range loss of heterozygosity (LOH) due to recombination was similar following passage in vivo and in vitro. We concluded that conditions encountered during infectious growth affect chromosome (Chr) disjunction more strongly than they affect mitotic recombination processes and that the differing spectrum of short- and long-range LOH events must reflect a difference in the selective environment represented by in vitro versus in vivo propagation. We are just beginning to understand how C. albicans adapts to varying host environments, whether adaptations are triggered by the host, and how the fungus modulates antigenicity through variations in its surface proteins. Our goal is to better understand what is necessary to maintain the pathogen-host balance from the perspective of the fungus, and to identify changes that will tip this balance towards pathogenicity. Recently, we showed that high levels of genetic change in C. albicans after exposure to a mouse host resulted in noticeable alterations in phenotype, including phenotypes associated with virulence. In this proposal we seek to understand how the high levels of genetic and phenotypic variation that we find in such strains affect the fitness of the fungus, and how these alterations in fitness influence host-pathogen interactions. We will continue our study of two sets of isolates from an oropharyngeal candidiasis (OPC) model and a blood stream infection (BSI) model to address several important questions in this proposal: 1) What are the genomic changes that lead to alterations in major virulence-associated phenotypes? 2) How do genetic changes arising in one host environment affect the ability to adapt to a new host niche? 3) How well does in vitro fitness correlate with in vivo fitness? and 4) Are there specific genotypes that allow preferential colonization of particular organs? These studies will advance our understanding of host-pathogen interactions from the pathogen perspective and will help reveal how the host and the fungus maintain their balanced relationship in healthy individuals as well as how disruption of this interaction causes devastating infections in the immuno-compromised host.